The 5’ fusion partner modulates response to the STAMP inhibitor asciminib in ABL -rearranged ALL

ABL -rearranged ( ABL r) acute lymphoblastic leukaemia (ALL) is associated with high rates of treatment failure and relapse and novel treatments are required. We investigated activity of the STAMP inhibitor asciminib in non- BCR::ABL1 ABL r ALL. The most common fusion in ABL r ALL is NUP214::ABL1 , which is associated with aggressive disease. For the first time we establish asciminib activity in three pre-clinical patient derived xenograft models of NUP214::ABL1 ALL. Treatment with asciminib reduced NUP214::ABL1 leukaemic burden, splenomegaly and ABL1 kinase activation. We observed significantly increased survival outcomes in asciminib-treated versus control mice. Additionally, site directed mutagenesis, in vitro cell death assays and in silico structural modeling defined a region of the ABL1 SH3 domain critical for asciminib efficacy and necessary for mediation of allosteric inhibition. Our findings establish asciminib as a potential treatment for NUP214::ABL1 ALL, significantly expanding the number of ALL patients who may benefit from asciminib therapy which has an excellent safety and tolerability profile.